What Do Diabetes, Islet Cells & Autoimmunity Have in Common?

“Man may be the captain of his fate, but he is also the victim of his blood sugar.” —Wilfrid Oakley, MB BChir, an early pioneer in diabetes care

Perusing the list of the most notable medical achievements in the 20th century, a reader may conclude that the discovery of insulin should rank in a category by itself. Consider some of its competitors: penicillin, discovered by Sir Alexander Fleming, MBBS, a brilliant Scottish bacteriologist noted for his original thinking and technical ingenuity throughout his illustrious career; the polio vaccine developed by Jonas Salk, MD, who had long studied viral diseases and focused his career on this particular virus for several years before his groundbreaking discovery; or the DNA double-helix structure discovered by a gifted, varied group of investigators working at Cambridge University in England, including James Watson, PhD (zoologist), Francis Crick, PhD (biologist), and Rosalind Franklin, PhD (chemist).

In stark contrast, consider the two people whose names are inextricably linked with the discovery of insulin: Frederick Banting, MD, was a struggling orthopedic surgeon who, for financial reasons, abandoned a fledgling private practice in London, Ontario, Canada, to pursue research in diabetes despite his lack of any formal training in the topic, and Charles Best, a 22-year-old medical student at the University of Toronto, Ontario, who was vying with a classmate to work on this project and succeeded by winning a determining coin toss.¹ (Interestingly, decades later, the losing student, E. Clark Noble, MD, had a second brush with fame, when he was mailed a bag of leaves from a Jamaican plant by a patient who was visiting the island and had heard about their medicinal effects on diabetes. Dr. Clark Noble passed them along to his brother, Robert Noble, MD, who directed a research lab at the University of Western Ontario in London. The leaf extracts showed little effect on blood glucose levels, but significantly suppressed bone marrow tissue. Subsequent work identified the primary ingredient as the vinca alkaloid, vinblastine, which remains a mainstay in cancer chemotherapy.)

Dr. Banting and Mr. Best were hardly the first investigators to try to extract the hormone responsible for glucose regulation from the pancreas. Prior efforts to inject subjects with crude pancreatic extracts were abject failures that led to abscess formation and fatal infections. These concoctions were loaded with the digestive enzymes, amylase and lipase that masked the tiny volume of secretions from the islets of Langerhans. Scientists were certain that these secretions contained the elusive glucose-regulating hormone, but were stymied by how to isolate it from the pancreatic slurry.

Dr. Banting conceived of ligating the pancreatic duct as a way of destroying the organ’s exocrine tissue that could provide a cleaner collection of the remaining islet cells and their extract, which he called isletin. Dr. Banting and Mr. Best set off to test this theory. They were aided by JJR MacLeod, MD, a prominent physiologist at the University of Toronto, Ontario, who provided them with lab space and 10 research dogs for experimentation before departing for a summer-long trip to Europe.³

The results were startling. Armed with a few syringes, Dr. Banting and Mr. Best moved from bed to bed on the pediatric ward where diabetic children were wasting away, injecting each child with their precious extract of isletin.⁴ They had nothing to lose. In 1922, a child diagnosed with type 1 diabetes carried a life expectancy of only two years. Their pro­ject met with fits and starts; different batches of the extract displayed different potencies. The purification process was further hampered by the strict regulation of alcohol during Prohibition.³ Fortunately, the development of the isoelectric precipitation method led to cleaner, more potent animal insulins, the appellation given to the purer form of isletin.

Word of their incredible discovery quickly spread across the globe. In a matter of just a few years, commercial-grade insulin saved countless lives. The 1923 Nobel Prize in Medicine was awarded to Drs. Banting and MacLeod, a bitter pill for some, considering that Dr. MacLeod was ensconced in Europe for a critical part of insulin’s discovery.³ A final footnote: Dr. Banting and Mr. Best sold their patent rights to insulin to the University of Toronto for a mere $3. Those were the days!

Under the Autoimmune Umbrella

The cause of type 1 diabetes remains unknown. What triggers the selective loss of the islet β cells that results in the dramatic underproduction of insulin? Because diabetes is no longer a fatal illness, scant pathological material exists to study and the enzyme-laden pancreas does not take kindly to needle biopsy procedures. What we do know is that in the early stages of diabetes, an intense inflammatory infiltrate in the pancreas seeks out and destroys islet cells. In fact, clinicians were aware of this hypothesis over a century ago, when salicylates were used to treat diabetes.⁵

Islet cells lack the ability to regenerate, so efforts to suppress the earliest stages of the type 1 diabetes immune response have met with failure. Consider that a panoply of treatments, including cyclosporine, cyclophosphamide, anti-CD-3 antibodies and, more recently, abatacept, have met with failure.⁶ Although co-stimulation modulation with abatacept temporarily slowed the reduction in β cell function in patients with newly diagnosed type 1 diabetes, this improvement lagged with continued administration, and eventually, the drug proved to be no better than placebo.⁷ Similarly, the initial hopes raised by the early success with islet cell transplantation faded. Normal endocrine reserve is not usually achieved in most cases because insulin independence is gradually lost over time.⁸

If type 1 diabetes cannot be cured, can it be identified during its preclinical state? Over the years, several intriguing epidemiologic clues have emerged. For example, the risk of developing type 1 diabetes depends on where you live. It is a rare condition in India, China and Venezuela. Compared with neighboring Estonia, being a resident of Finland raises one’s risk of type 1 diabetes three-fold.⁶ In many different countries, children under the age of 5 who were born in the spring carry the greatest risk of developing the disease.

Could the development of type 1 diabetes be related to a dietary issue? A Finnish study identified 230 infants with a first-degree relative with type 1 diabetes and randomly assigned infants to receive a hydrolyzed infant formula or conventional formula whenever breast milk was not available during the first 6 to 8 months of life. The investigators sought to measure the development of autoantibodies to islet cells, a finding that is strongly correlated with the subsequent development of diabetes. Children who received the hydrolyzed formula were less likely to develop two or more islet autoantibodies, compared with those who received the conventional formula, with a hazard ratio of 0.52.⁹

Among the autoantibodies targeting islet cells is one of particular interest that also targets the neuronal enzyme, glutamic acid decarboxylase (GAD). Antibodies to GAD are detected not only in individuals with a strong susceptibility to developing diabetes or in their first-degree relatives, but it is intriguing to note that about two-thirds of individuals afflicted with the rare autoimmune movement disorder, stiff person syndrome, carry this antibody, too, albeit in far higher concentrations.¹⁰ Knocking out neuronal pathways that are critical to inhibiting motor function is analogous to losing the brake mechanism that prevents our muscles from overcontracting and developing severe spasm. These patients often have great difficulty performing simple motor activities. Many of them develop type 1 diabetes and an assortment of other autoimmune conditions, including pernicious anemia, vitiligo and Hashimoto’s thyroiditis.

Why GAD, an enzyme that is restricted to the central nervous system, has found its way into the pancreas where it serves as an antigen target in the prediabetic state remains a mystery of human development.

Because diabetes is no longer a fatal illness, scant pathological material exists to study & the enzyme-laden pancreas does not take kindly to needle biopsy procedures.

Linking Fat with Inflammation

Room’s Studio/shutterstock.com

Although the case confirming a critical role for autoimmunity in the pathogenesis of type 1 diabetes is settled, the evidence supporting its relevance in the development of type 2 diabetes is only starting to emerge. This form of diabetes is sweeping the globe and accounts for over 95% of cases.

Type 2 diabetes appears to require some critical immune perturbations in its earliest stages for it to develop into a full-blown metabolic disorder. This begins with the understanding that obesity initiates a profound immune response by recruiting large numbers of macrophages to adipose tissue, accounting for as many as 40% of the cells residing in fat. Chronic caloric excess leads to adipose tissue expansion and enlarging adipocytes secrete chemokines that stimulate even more macrophage migration, initiating the tissue inflammatory response. These macrophages churn out tumor necrosis factor (TNF), a cytokine well known to us that can induce hyperglycemia, stimulate fat production and increase resistance to the effects of insulin and its pro-inflammatory ally, interleukin 1 (IL-1). Together, these cytokines generate the systemic inflammatory response that can be so destructive in type 2 diabetes, one that extends beyond fat cells to involve the pancreas, liver, muscle tissue and the cardiovascular system and results in considerable morbidity.¹¹

What if we turn off this inflammatory cascade? A recent retrospective study by some of our colleagues found that patients with rheumatoid arthritis and psoriasis treated with TNF inhibitors had a significantly decreased risk of developing type 2 diabetes compared with patients taking other anti-rheumatic drugs, suggesting that anti-TNF strategies may be effective in disease prevention.¹² Interestingly, hydroxychloroquine showed a similar benefit.

The immune-suppression benefit may extend to some of the drugs being used to manage type 2 diabetes. In one study of 50 obese patients with multiple sclerosis (MS), it was observed that metformin and pioglitazone reduced MS disease activity as measured by brain MRI. Moreover, both treatments decreased the secretion of TNF and IL-6 and increased the numbers and regulatory properties of T regulatory cells.¹³ In disorders of autoimmunity, one should no longer consider obesity to merely be a passive bystander, away from the fray.¹⁴ It’s time to get tough on fat!

In 1922, a child diagnosed with type 1 diabetes carried a life expectancy of only two years.

The Big Picture

The rules of autoimmunity prevail for diabetes as they do for most rheumatologic disorders. The similarities are obvious: Although we can identify the elegant complexity of the immune response following the inception of type 1 diabetes, we are at a loss to explain what initiates the immune cascade that destroys the islet cells. Although the target cell has been identified, the best therapies available can only replenish the missing hormone, insulin. Although insulin pumps are getting better at controlling blood glucose, no technology will replace a normally functioning pancreas. And sadly, islet cell transplantation has been a bust.

Sorting through the pathogenesis of type 2 diabetes, we have discovered that being overweight sets off a cascade of immune responses that accelerate the creation of a full-blown metabolic crisis.

It is not for lack of trying that a cure for either form of diabetes is lacking. Yes, insulin can replace what is missing in type 1 diabetes, and some of the drugs used in type 2 diabetes may help dampen aberrant immune responses. But curing diabetes is not likely to happen in the foreseeable future. Sound familiar?

It has been longer than 100 years since famed German bacteriologist Paul Ehrlich, MD, coined the term, horror autotoxicus, to describe the damaging effects of the autoimmune response when self attacks self.¹⁵ Whether it be diabetes, rheumatoid arthritis, lupus or multiple sclerosis, how to reverse the ravages of these self-inflicted wounds and restore our tissues to homeostasis continues to elude us.

Simon M. Helfgott, MD, is associate professor of medicine in the Division of Rheumatology, Immunology and Allergy at Harvard Medical School in Boston.

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